Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration of cognitive function and loss of memory in association with widespread neuronal death. Currently, however, there are no effective medications to cure or treat AD. Endocannabinoids (eCBs) are endogenous lipid signaling mediators involved in a variety of physiological, pharmacological, and pathological processes and capable of modulating synaptic transmission and plasticity by activation of the cannabinoid receptor (CB1R), a predominantly expressed type of cannabinoid receptors in the brain. Growing evidence suggests that 2- arachidonoylglycerol (2-AG), the most abundant eCB and a full agonist for CB1 and CB2 receptors, renders anti-inflammatory and neuroprotective properties. Neuroinflammation is at the root of many chronic neurological and mental disorders and is believed to contribute to the pathogenesis of neurodegenerative diseases such as AD. However, little is known about whether 2-AG plays an important role in production of beta-amyloid, the hallmark of AD, and beta-amyloid-induced synaptic and memory deficits. The goal of the proposed project is to understand the role of 2-AG in development and neuropathology of AD. In this exploratory study application, we will test our hypothesis that inhibition of monoacylglycerol lipase (MAGL), an enzyme that hydrolyzes 2-AG, is able to prevent and reduce synthesis of A2 and alleviate neuropathology in an animal model of AD. This hypothesis will be tested by accomplishing three specific aims: Aim 1: To test the hypothesis that elevation of endogenous 2-AG is capable of reducing or slowing production and deposition of beta-amyloid in the brain of APP transgenic mice;Aim 2: To test the hypothesis that inhibition of MAGL is able to inhibit neuroinflammation and prevent neurodegeneration in APP transgenic animals;Aim 3: To test the hypothesis that inhibition of MAGL is able to prevent or rescue deficits in long-term synaptic plasticity and cognitive function in APP transgenic mice. The proposed application will tackle a novel and intriguing topic that endogenous 2-AG is crucial in neuropathology of AD. The results generated from this application will not only provide experimental evidence that inhibition of MAGL is capable of slowing or decreasing synthesis and accumulation of beta-amyloid, ameliorating beta-amyloid-induced synaptic and memory deficits, and preventing neurodegeneration, but also indicate that approaches that elevate endogenous 2-AG by inhibiting its hydrolysis or facilitating its synthesis are new efficacious therapeutic interventions for preventing, alleviating or treating Alzheimer's disease. PUBLIC HEALTH RELEVANCE: The proposed application will tackle a novel and intriguing topic that naturally occurring 2-AG is crucial in neuropathology of AD. The results generated from this application will not only provide experimental evidence that inhibition of MAGL is capable of slowing or decreasing synthesis and accumulation of A2, ameliorating A2- induced synaptic and memory deficits, and preventing neurodegeneration, but also indicate that approaches that elevate endogenous 2-AG by inhibiting its hydrolysis or facilitating its synthesis are new efficacious therapeutic interventions for preventing, alleviating or treating Alzheimer's disease.